Synthesis of fluorine-containing 1,10-phenanthrolines using mild versions of Skraup and Doebner-von Miller reactions

Article abstract of DOI:10.1016/j.jfluchem.2016.11.016

A versatile route for the synthesis of new 1,10-phenanthroline derivatives with fluorine-containing groups is described. Skraup reactions were performed with yields of 19 up to 48% and overall yields of 5 up to 13% based on different fluorinated anilines as starting materials. Ten formerly unknown derivatives were synthesized and characterized by NMR spectroscopy (¹H,¹³C,¹⁹F), ESI mass spectrometry and elemental analysis.

Full text of DOI:10.1016/j.jfluchem.2016.11.016

Accepted Manuscript
Title: Synthesis of fluorine-containing 1,10-phenanthrolines
using mild versions of Skraup and Doebner-von Miller
reactions
Author: Carsten Lu¨dtke Axel Haupt Martin Wozniak Nora
Kulak
PII:
S0022-1139(16)30228-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.11.016
FLUOR 8903
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1-8-2016
21-11-2016
21-11-2016
Please cite this article as: Carsten Lu¨dtke, Axel Haupt, Martin Wozniak, Nora
Kulak, Synthesis of fluorine-containing 1,10-phenanthrolines using mild versions
of Skraup and Doebner-von Miller reactions, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2016.11.016
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Synthesis of fluorine-containing 1,10-phenanthrolines using mild versions of
Skraup and Doebner–von Miller reactions
Carsten Lüdtke, Axel Haupt, Martin Wozniak, Nora Kulak*
Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany.
1

Graphical abstract
Highlights
 Fluorinated 1,10-phenanthroline and 2-methyl-1,10-phenanthroline
derivatives have been synthesized and characterized
 Functional groups comprise F, CF3, SCF3, OCF3 and SF5 at
position 5 as well as F in positions 5 and 6 of the phenanthroline
moiety
 Skraup and Doebner-von Miller reactions allowed access to ten
new phenanthroline derivatives comprising one formerly reported
impossible to synthesize
Abstract: A versatile route for the synthesis of new 1,10-phenanthroline derivatives with fluorine
containing groups is described. The Skraup reactions were performed with yields of 19 up to 48% and
overall yields of 5 up to 13% based on different fluorinated anilines as starting materials. Ten formerly
unknown derivatives were synthesized and characterized by NMR spectroscopy (1H, 13C, 19F), ESI mass
spectrometry and elemental analysis.
Keywords: phenanthroline; quinoline; Skraup reaction; Doebner–von Miller reaction
1. Introduction
The Skraup reaction was first described in 1880 by Z. Skraup for the synthesis of quinoline starting
from aniline.[1] Applying this reaction scheme on 8-aminoquinolines, it is possible to construct
1,10-phenanthrolines. The general phenanthroline scaffold consists of three annulated rings, two
pyridine and one phenyl ring, representing a chelating ligand for many metal ions.
Phenanthroline finds applications in redox indicators and in catalysis. It is used as a titration agent for
organometallic magnesium and lithium compounds.[2–5] Its coordination properties allow the
stabilization of unusual oxidation states depending on the substitution motif on the phenanthroline
2

scaffold.[6,7] Based on its planar structure it is used as a DNA intercalator, where it promotes a short
distance between metal centres and DNA strands.[8–10]
Substituents affect the properties of the 1,10-phenanthroline ligand with regard to the metal centre
or even the whole complex, for example the redox potentials and lipophilicity. One possibility to do
so is the introduction of fluorine-containing groups which are widely used to modify organic
molecules and tune their biochemical activity, particularly for pharmaceutical applications.
Phenanthroline and the related N,N-heterocyclic ligand bipyridine were functionalized with various
fluorine-containing groups before. For example, 4-fluorophenyl and 4’-trifluoromethyl-biphenyl
groups were attached to phenanthroline[11], and 4,4’-bipyridine carrying eight fluorine substituents
was synthesized [12]. 2,2’-Bipyridine with fluorinated alkyl groups was discussed for potential use as
a ligand for transition metals in fluorous biphasic catalysis [13,14].
Interestingly, only three derivatives where fluorine or fluorine-containing substituents are DIRECTLY
bound to the middle phenyl ring of 1,10-phenanthroline are known in the literature: 5-fluoro-, 5,6-
difluoro and 5-trifluoromethyl-1,10-phenanthroline.[15–18] The trifluoromethyl derivative and its
electronic properties were accessible only theoretically via DFT calculations.[17] Previous attempts to
synthesize this analogue failed.[19] The 5,6-difluoro analog was synthesized via a reaction of
unsubstituted o-phenanthroline in a triethylamine/HF mixture, whereas 5-fluoro phenanthroline was
obtained from 5-amino quinoline as a starting material via 8-amino-5-fluoro quinoline in a Skraup
reaction.[15,16]
2. Results and discussion
2.1. Fluorine containing 1,10-phenanthrolines
First attempts to synthesize the trifluoromethylated 1,10-phenanthroline via Skraup reaction
conditions starting with 8-amino-5-trifluoromethyl quinoline failed due to the hydrolysis of the CF3
group by concentrated sulfuric acid at elevated temperatures and long reaction times.[19] By
exchanging glycerol and nitrobenzene (as suggested in the original protocol) with acrolein diethyl
acetal (ADEA) and arsenic pentoxide it was possible to lower the reaction temperature and shorten
the reaction time for the synthesis of 8-amino-5-fluoroquinoline starting from 5-fluoro-2-
nitroaniline.[20] Using these reaction conditions for the synthesis of 5-trifluoromethyl-1,10-
phenanthroline the CF3 group stayed unaffected and no hydrolysis was observed.
We employed the above described conditions for the synthesis of several fluorine containing 8-
nitroquinoline derivatives starting from commercially available 2-nitroanilines 1 (Scheme 1) with
exception of the SF5 analogue 1e, which was not purchasable, and had to be synthesized first.[21]
Subsequently, the 8-nitro quinoline compounds 2a–e were reduced to the corresponding amines 3a–
e with stannous chloride dihydrate in concentrated hydrochloric acid. A second Skraup reaction was
applied to form the fluorinated 1,10-phenanthrolines 4a–f from the 8-amino quinolines 3a–f
(Scheme 1). For 4f, the respective precursor 2f was obtained by regioselective nitration of 5-
trifluoromethylthio quinoline with KNO3 (in H2SO4) in position 8. The latter quinoline compound was
obtained by reduction of 5-nitro quinoline and conversion of the respective amine according to the
literature under Sandmeyer conditions with the Ruppert-Prakash reagent (Me3Si-CF3) [22]. Footnote:
Details regarding the synthesis of 2f can be found in the Experimental Section.
The purification of phenanthrolines 4a–f was easily performed by column chromatography and
subsequent sublimation. Yields ranged from 19 to 41% for the Skraup reaction and up to 92% for the
reduction step, resulting in overall yields of up to 13% based on the anilines. The yield turned out to
be very sensitive to the amount of oxidation agent and the concentration of acid, e.g. an elevated
amount of arsenic(V) oxide (> 0.25 eq.) decreased the yield dramatically.
2.2. Fluorine containing 2-methyl-1,10-phenanthrolines
3

Several 2-methylphenanthrolines were synthesized in order to offer an additional feature for
derivatization like aliphatic radical halogenation or hydroxylation. The synthetic pathway was via a
Doebner–von Miller reaction by exchanging the acrolein diethyl acetal with croton aldehyde.[23]
Reaction conditions were equal to the Skraup reaction described above (Scheme 2). Due to very low
yields for the reduction of methylated quinolines with stannous chloride in hydrochloric acid (up to
25% vs. 92% for the non-methylated species, vide supra) this step was performed with hydrazine
hydrate and palladium on activated charcoal as a catalyst (Scheme 2). This reaction was very
sensitive to the quantity of catalyst and the reaction temperature possibly due to side reactions like
hydrodefluorination. The best results were achieved at lower temperatures (68 °C vs. 78 °C) and a
maximum amount of 0.1 mol% catalyst. Enhancing the portion of Pd/C to more than 0.1 mol% or
raising the reaction temperature to more than 68 °C increased the amount of hydrodefluorination
product (8-amino-2-methylquinoline), for the reduction of fluorinated 2-methyl-8-nitroquinoline (5a)
up to 40%. In the case of SF5-substituted 2-methyl-8-nitroquinoline (5e) the reaction time had to be
extended due to incomplete reduction with hydroxylamine as a side product. The hydroxylamine
could be converted, however, with a high yield to the amine.
The Doebner–von Miller and Skraup reactions can be arbitrarily combined. Thus it was possible to
synthesize different 5- or 6-substituted 2-methyl-1,10-phenanthrolines and a fluorine-containing
neocuproine derivative (2,9-dimethyl-1,10-phenanthroline) (Scheme 2). Five new fluorinated 2-
methyl-1,10-phenanthrolines (7a,c,e and 8a,f) and 5-fluoroneocuproine 9 were synthesized in
acceptable to good yields (19 to 48%) for Doebner–von Miller and Skraup reaction, respectively, and
excellent yields (78 to 89%) for the reduction with Pd/C and hydrazine hydrate. All synthesized
compounds are listed in table 1.
3. Conclusion
We have investigated the formation of fluorine-containing 1,10-phenanthroline derivatives via a
modification of the Skraup reaction. With this method we were able to synthesize ten formerly
unknown compounds. Furthermore, we succeeded in synthesizing 5-trifluoromethyl-1,10-
phenanthroline, a compound previously described as impossible to synthesize using Skraup reaction
conditions due to the lability of the trifluoromethyl group.[19] The used method was mild enough to
leave substituents unaffected. The scope was broad, including derivatives containing fluorine, CF3,
SCF3, OCF3 and SF5 groups and the yields for Skraup synthesis were moderate to good. Furthermore
we have synthesized methylated derivatives to allow another position for functionalisation of the
phenanthroline scaffold.
4. Experimental
4.1. General information
1H and 13C NMR spectra were recorded in deuterated chloroform (internal reference) on a Jeol JNM-
ECS 400 FT-NMR and Bruker AVANCE III 700, respectively. 19F NMR spectra (CFCl3 as external
standard) were recorded on a Jeol JNM-ECS 400 FT-NMR. Chemical shifts (δ) are reported in ppm and
coupling constants (J) in Hertz (Hz). Abbreviations for multiplicities are: s = singlet, d = doublet, t =
triplet, q = quartet, quin = quintet, m = multiplet. HRMS-ESI(+) spectra were obtained on an Agilent
6210 ESI-ToF, Agilent Technologies. The flow rate and the spray voltage were 4 μL/min and 4 kV,
respectively. The desolvation gas was set at 1 bar. Elemental analyses were performed on a
Elementar Vario EL. IR spectra were recorded on a Nicolet Avatar 320 FT-IR instrument. All reagents
and starting materials were purchased from commercial sources and used without further
purification.
4

Generally, the purification for 8-nitroquinolines included column chromatography (hexane/ethyl
acetate = 3/1) on silica. 8-Aminoquinolines were obtained via alkaline precipitation (adjustment to
pH = 14 with 10 M aqueous NaOH solution) and excessive washing with water. The purification for
phenanthroline derivatives included column chromatography (ethyl acetate/isopropyl amine = 20/1)
on silica, followed by sublimation in high vacuum.
4.2. Synthesis
Reaction type A (exemplarily for 1b): The reaction was performed according to a literature known
procedure.[20] Aniline 1b (5.0 g, 29 mmol) and arsenic pentoxide hydrate (4.5 g, 5.8 mmol) were
dissolved in a mixture of sulfuric acid (15 mL) and water (9 mL). This solution was heated up to 80 °C
and at constant temperature acrolein diethyl acetal (6.2 mL, 41 mmol) was added dropwise during
3 h with a syringe pump. After completion of addition the solution was heated up to 120 °C for
90 min with vigorous stirring. The mixture was allowed to cool down, was poured onto an ice/water
mixture (100 mL) and the resulting suspension was filtered. Aqueous ammonia was added dropwise
to the filtrate till reaching pH ≈ 6. The crude mixture was extracted with dichloromethane (3 x 50
mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. 2b was obtained as
a yellow solid after sublimation (70 °C/2*10-2mbar) of the crude product in 33% yield (2.0 g, 9.5
mmol).
Reaction type B (exemplarily for 2b): The reaction was performed according to a literature known
procedure.[20] Stannous chloride dihydrate (5.6 g, 25 mmol) was dissolved in concentrated HCl (32%,
30 mL) and cooled in an ice/water bath. A solution of quinoline 2b (1.3 g, 6.2 mmol) in concentrated
HCl (32%, 12 mL) was added dropwise to the reaction solution during 20 min under vigorous stirring
and cooling. The resulting mixture was continuously stirred for 60 min under cooling (< 5 °C) and
additionally for 3 h at room temperature. After adding water (200 mL) the solution was basified
(pH = 14) with 10 M NaOH, filtrated and the precipitate was washed with water. After drying, 3b was
obtained as a colorless solid in 63% yield (0.7 g, 3.9 mmol).
Reaction type C (exemplarily for 1a): Aniline 1a (10.0 g, 64 mmol) and arsenic pentoxide hydrate
(9.7 g, 12 mmol) were dissolved in a mixture of sulfuric acid (30 mL) and water (18 mL). This solution
was heated up to 70 °C. Croton aldehyde (8.0 mL, 97 mmol) was added dropwise during 3 h with a
syringe pump while the temperature was kept constant at 70 °C. After completion of addition the
solution was heated up to 120 °C for 90 min with vigorous stirring. The mixture was allowed to cool
down, was poured onto an ice/water mixture (150 mL) and the resulting suspension was filtered.
Aqueous ammonia was added dropwise to the filtrate till reaching pH ≈ 6. The crude mixture was
extracted with dichloromethane (3 x 100 mL). The organic phase was washed with brine and dried
over anhydrous Na2SO4. Column chromatography (hexane/ethyl acetate = 3/1) afforded 5a as a
yellow solid in 28% yield (3.7 g, 18 mmol).
Reaction type D (exemplarily for 5a): Quinoline 5a (3.7 g, 18 mmol) was dissolved in ethanol (200 mL)
and Pd/C (10%, 250 mg, 0.2 mmol) was added. After stirring for 10 min, a solution of an excess
hydrazinium hydroxide (13 mL, 265 mmol) in ethanol (65 mL) was added dropwise to the mixture
during 60 min. The suspension was heated to 65 °C for 5 h. After cooling down it was filtered and the
solvent was removed with a rotary evaporator. The residue was dried in high vacuum and, without
further purification, 6a was obtained as a light yellow solid in 78% yield (2.5 g, 14 mmol).
8-Nitro-5-(trifluoromethylthio) quinoline (2f):
5-Amino quinoline: 5-Nitro quinoline (2.05 g, 11.8 mmol) and Pd/C (10%) (0.64 g, 0.6 mmol) were
suspended in 90 mL ethanol. The suspension was heated to reflux and hydrazinium hydroxide (2.9
mL, 57.5 mmol) in 50 mL ethanol was added during 60 min. Subsequently, the mixture was stirred for
5

16 h at constant temperature, filtered hot and the filtrate was concentrated under reduced pressure.
Column chromatography on silica gel (ethyl acetate/petroleum ether (3:1)) afforded 5-amino
quinoline as a colorless solid in 60% yield (1.02 g, 7.1 mmol).
5-(Trifluoromethylthio) quinoline: HBF4 (3.1 mL, 24.7 mmol) and isoamyl nitrite (4.1 mL, 30.4 mmol)
were added to a solution of 5-amino quinoline in 90 mL ethanol while keeping the temperature
below 5 °C. After 3 h stirring the mixture was cooled in an ice-water bath, and diethyl ether (20 mL)
was added. Subsequently, the mixture was stored overnight at -20 °C. The resulting suspension was
filtered, and the red solid was washed with a mixture ethanol/diethyl ether (1:10, 40 mL). 5-
(Diazonium)chinolinyl tetrafluoroborate was dried under air (2.26 g, 9.3 mmol, 93% yield) and was
used without further purification for the subsequent reaction. Under argon atmosphere, CuSCN (0.25
g, 2.1 mmol), NaSCN (0.5 g, 6.1 mmol), and Cs2CO3 (2.7 g, 8.3 mmol) were added to 16 mL
acetonitrile and the resulting suspension was stirred for 10 min. A solution of 5-(diazonium)chinolinyl
tetrafluoroborate (1 g, 4.1 mmol) in 16 mL acetonitrile was added dropwise to the suspension.
Subsequently, Me3SiCF3 was added dropwise and the solution was stirred for 16 h at room
temperature. The resulting mixture was filtered over approx. 10 g Celite. The Celite pad was washed
with 3 x 10 mL diethyl ether. The filtrate was washed with water and brine, and dried over anhydrous
Na2SO4. Column chromatography on silica gel (diethyl ether) afforded 5-(trifluoromehtylthio)
quinoline as a colorless solid in 61% yield (0.57 g, 2.5 mmol).
8-Nitro-5-(trifluoromethylthio) quinoline: 5-Trifluoromethylthio quinoline (0.57 g, 2.5 mmol) was
dissolved in sulfuric acid (2.0 mL). The solution was kept in an ice-water bath, when KNO3 (0.33 g, 3.3
mmol) was added in portions during 90 min. This mixture was stirred at room temperature for 17 h,
and subsequently mixed with ice. The product was extracted with ethyl acetate (3 x 30 mL) and the
organic layer was dried over anhydrous Na2SO4. Column chromatography (hexane/ethyl acetate =
1:2…0.1) afforded 2f as a yellow solid in 76% yield (0.53 g, 1.9 mmol).
4.3. Characterization of products
All phenanthroline products were characterized by 1H, 13C and 19F NMR, HRMS (ESI+), and CHNS
analysis. For precursors and intermediates at least 1H and 19F NMR are given, supplemented by IR
(ATR) and HRMS (ESI+) data.
Chemical shifts of phenanthroline derivatives can vary and move up to 0.4 ppm towards high field
with increasing concentration of the ligand (concentration range between 0.06 and 1.00 mM). Similar
observations were made for other aromatic systems like quinolines.[24] Reported NMR data of
phenanthroline derivatives were thus measured at concentrations between 0.3 and 1.0 mM. The
numbering scheme for carbon atoms is shown below:
5-Fluoro-8-nitro quinoline (2a, CAS 152167-85-6) [20] (reaction type A)
Yellow solid. 1H NMR (CDCl3, 400 MHz): δ 9.15 (dd, J = 4.2, 1.7 Hz, 1H, H-2), 8.53 (dd, J = 8.5, 1.7 Hz,
1H, H-4), 8.13 (dd, J = 8.5, 5.2 Hz, 1H, H-7), 7.64 (dd, J = 8.6, 4.2 Hz, 1H, H-3), 7.30 (dd, J = 8.6 Hz, 1H,
H-6). 19F NMR (CDCl3, 376 MHz): δ -112.30 (dd, J = 8.6, 5.2 Hz). In [20] 1H NMR are given and agree
with the data presented here.
8-Amino-5-fluoro quinoline (3a, CAS 161038-18-2) [20] (reaction type B)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 8.79 (dd, J = 4.2, 1.6 Hz, 1H, H-2), 8.32 (dd, J = 8.4, 1.6 Hz,
1H, H-4), 7.40 (dd, J = 8.4, 4.2 Hz, 1H, H-3), 7.02 (dd, J = 9.8, 8.4 Hz, 1H, H-6), 6.78 (dd, J = 8.3, 4.9 Hz,
1H, H-7), 4.84 (s, 2H, NH2). 19F NMR (CDCl3, 376 MHz): δ -137.27 (dd, J = 9.8, 4.9 Hz). In [20] 1H NMR
are given and agree with the data presented here.
5-Fluoro-1,10-phenanthroline (4a, CAS 191861-19-5) (reaction type A)
6

Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 9.25 (dd, J = 4.3, 1.7 Hz, H-2), 9.14 (dd, J = 4.3, 1.7 Hz,
H-9), 8.53 (dd, J = 8.2, 1.7 Hz, H-4), 8.19 (dd, J = 8.1, 1.7 Hz, H-7), 7.71 (dd, J = 8.3, 4.4 Hz, H-3), 7.63
(dd, J = 8.1, 4.3 Hz, H-8), 7.43 (d, J = 10.2 Hz, H-6). 13C NMR (CDCl3, 176 MHz) δ 154.9 (d, J = 256.2 Hz,
C-5), 150.5 (s, C-2), 148.8 (d, J = 2.2 Hz, C-9), 146.1 (d, J = 4.9 Hz, C-12), 143.0 (s, C-11), 134.8 (d, J =
5.6 Hz, C-7), 128.7 (d, J = 4.9 Hz, C-4), 127.3 (d, J = 10.8 Hz, C-6a), 122.8 (s, C-8), 122.4 (s, C-3), 120.5
(d, J = 19.5 Hz, C-4a), 106.9 (d, J = 20.5 Hz, C-6). 19F NMR (CDCl3, 376 MHz): δ -123.48 (d, J = 10.2 Hz).
HRMS (m/z, ESI+): 199.069 (calcd.: 199.067) [M+H]+, 221.049 (calcd.: 221.049) [M+Na]+. CHN analysis
(%): C 72.59 (calcd.: 72.72), H 3.74 (3.56), N 14.16 (14.13). Using a different procedure, 4a has been
described and characterized by 1H NMR in [15]. These data are consistent.
5,6-Difluoro-8-nitro quinoline (2b, CAS 1394083-87-4) (reaction type A)
Yellow solid. 1H NMR (CDCl3, 400 MHz): δ 9.12 (dd, J = 4.3, 1.6 Hz, H-2), 8.54 (dd, J = 8.6, 1.4 Hz, H-4),
8.09 (dd, J = 9.1, 7.4 Hz, H-7), 7.68 (dd, J = 8.7, 4.2 Hz, H-3). 19F NMR (CDCl3, 376 MHz): δ -136.56 (dd,
J = 18.9, 9.3 Hz, F-6), -138.07 (dd, J = 19.0, 7.4 Hz, F-5).
8-Amino-5,6-difluoro quinoline (3b, CAS 1242094-79-6) (reaction type B)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 8.74 (dd, J = 4.2, 1.6 Hz, H-2), 8.34 (dd, J = 8.5, 1.5 Hz, H-
4), 7.47 (dd, J = 8.5, 4.2 Hz, H-3), 6.72 (dd, J = 12.1, 7.2 Hz, H-7), 5.10 (s, NH2). 19F NMR (CDCl3, 376
MHz): δ -138.30 (dd, J = 20.5, 12.1 Hz, F-5), -164.37 (dd, J = 20.5, 7.0 Hz, F-6).
5,6-Difluoro-1,10-phenanthroline (4b, CAS 134023-57-7) (reaction type A)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 9.18 (d, 2H, J = 4.3 Hz, H-2 and H-9), 8.51 (dt, 2H, J = 8.3,
1.6 Hz, H-4 and H-7), 7.71 (dd, 2H, J = 8.3, 4.3 Hz, H-3 and H-8). 13C NMR (CDCl3, 101 MHz) δ 149.7 (s,
2C, C-2 and C-9), 142.5 (s, 2C, C-11 and C-12), 140.3 (dd, 2C, J = 257.0 Hz, 13.5 Hz, C-5 and C-6), 128.3
(s, 2C, C-4 and C-7), 122.8 (s, 2C, C-3 and C-8), 120.4 (dd, 2C, J = 11.2 Hz, 6.8 Hz, C-4a and C-6a). 19
F
NMR (CDCl3, 376 MHz): δ -150.65 (s, 2F). HRMS (m/z, ESI+): 217.059 (calcd.: 217.057) [M+H]+, 239.042
(calcd.: 239.039) [M + Na]+, 455.093 (calcd.: 455.089) [2M + Na]+. CHN analysis (%): C 67.02 (calcd.:
66.67), H 2.90 (2.80), N 12.98 (12.96). Using a different procedure, 4b has been described and
characterized by 19F NMR in [16]. These data are consistent.
8-Nitro-6-(trifluoromethyl) quinoline (2c, CAS 955413-30-6) (reaction type A)
Yellow solid. 1H NMR (CDCl3, 400 MHz): δ 9.19 (dd, J = 4.2, 1.5 Hz, H-2), 8.40 (dd, J = 8.4, 1.6 Hz, H-4),
8.37 (s, H-7), 8.21 (d, J = 1.8 Hz, H-5), 7.71 (dd, J = 8.4, 4.2 Hz, H-3). 19F NMR (CDCl3, 376 MHz): δ
-62.29 (s, 3F, CF3). HRMS (ESI+), m/z: 265.020 (calcd.: 265.020) [M+Na]+, 507.051 (calcd.: 507.050)
[2M+Na]+. IR (ATR): 3095 (w), 3068 (w), 2927 (w), 1640 (w), 1598 (w), 1575 (w), 1539 (s), 1501 (w),
1466 (m), 1435 (m), 1360 (m), 1341 (s), 1289 (s), 1224 (m), 1201 (m), 1164 (s), 1126 (s), 1083 (m),
1030 (m), 997 (w), 900 (m), 875 (m), 795 (m), 761 (m), 728 (w), 665 cm−1 (m).
8-Amino-6-(trifluoromethyl) quinoline (3c, CAS 955413-26-0) (reaction type B)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 8.86 (dd, J = 4.2, 1.6 Hz, H-2), 8.19 (dd, J = 8.3, 1.4 Hz, H-
4), 7.50 (dd, J = 8.3, 4.2 Hz, H-3), 7.44 (s, H-5/7), 7.05 (d, J = 1.8 Hz, H-7/5), 5.37 (s, 2H, NH2). 19F NMR
(CDCl3, 376 MHz): δ -62.75 (s, 3F, CF3). Using a different procedure, 3c has been described and
characterized by 1H NMR in [25]. These data are consistent.
5-(Trifluoromethyl)-1,10-phenanthroline (4c) (reaction type A)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 9.23 (dd, J = 4.4, 1.8 Hz, H-9), 9.21 (dd, J = 4.3, 1.6 Hz, H-
2), 8.50 (dquin, J = 8.5, 1.9 Hz, H-4), 8.26 (dd, J = 8.1, 1.8 Hz, H-7), 8.15 (s, H-6), 7.68 (dd, J = 8.5, 4.3
Hz, H-3), 7.65 (dd, J = 8.1, 4.4 Hz, H-8). 13C NMR (CDCl3, 101 MHz) δ 152.6 (s, C-9), 151.0 (s, C-2), 147.3
(s, C-10a), 146.4 (s, C-10b), 137.2 (s, C-7), 133.0 (q, 4JC-F = 2.5 Hz, C-4), 126.4 (q, 3JC-F = 6.0 Hz, C-6),
7

126.1 (s, C-6a), 124.1 (m, C-4a), 123.9 (s, C-8), 123.8 (q, 1JC-F = 273.8 Hz, CF3), 123.6 (s, C-3). 19F NMR
(CDCl3, 376 MHz): δ -60.01 (s, 3F, CF3). HRMS (ESI+), m/z: 249.064 (calcd.: 249.063) [M+H]+, 271.046
(calcd.: 271.045) [M+Na]+, 519.102 (calcd.: 519.101) [2M+Na]+. CHN analysis (%): C 62.88 (calcd.:
62.91), H 2.83 (2.84), N 11.22 (11.29).
8-Nitro-6-(trifluoromethoxy) quinoline (2d, CAS 1394083-86-3) (reaction type A)
Yellow solid. 1H NMR (CDCl3, 400 MHz): δ 9.09 (dd, J = 4.2, 1.7 Hz, H-2), 8.29 (dd, J = 8.4, 1.7 Hz, H-4),
7.92 (d, J = 2.5 Hz, H-7), 7.88 (dd, J = 2.4, 1.2 Hz, H-5), 7.64 (dd, J = 8.4, 4.2 Hz, H-3). 19F NMR (CDCl3,
376 MHz): δ -57.99 (s, CF3). HRMS (ESI+), m/z: 259.038 (calcd.: 259.033) [M+H]+, 281.017 (calcd.:
281.015) [M+Na]+, 539.042 (calcd.: 539.040) [2M+Na]+. IR (ATR): 3097 (w), 3064 (w), 1634 (m), 1599
(m), 1530 (s), 1497 (m), 1464 (w), 1372 (w), 1350 (m), 1272 (m), 1249 (m), 1213 (m), 1169 (s), 1131
(m), 1049 (m), 888 (m), 796 (m), 785 (m), 766 (m), 744 (w), 644 (m), 610 cm−1 (w).
8-Amino-6-(trifluoromethoxy) quinoline (3d, CAS 1394083-90-9) (reaction type B)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 8.75 (dd, J = 4.2, 1.7 Hz, H-2), 8.03 (dd, J = 8.3, 1.7 Hz, H-
4), 7.41 (dd, J = 8.3, 4.2 Hz, H-3), 6.96–6.92 (m, H-5/7), 6.75–6.71 (m, H-5/7), 5.18 (s, NH2). 19F NMR
(CDCl3, 376 MHz): δ -57.37 (s, CF3). HRMS (ESI+), m/z: 229.061 (calcd.: 229.059) [M+H]+, 251.040
(calcd.: 251.041) [M+Na]+. IR (ATR): 3471 (br w), 3352 (br w), 1618 (m), 1593 (m), 1507 (s), 1430 (w),
1385 (m), 1339 (w), 1250 (s), 1206 (s), 1140 (s), 1038 (w), 996 (w), 873 (w), 839 (m), 785 (m), 718 (w),
673 cm−1 (w).
5-(Trifluoromethoxy)-1,10-phenanthroline (4d) (reaction type A)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 9.25 (dd, J = 4.3, 1.7 Hz, 1H), 9.18 (dd, J = 4.3, 1.7 Hz, 1H),
8.54 (dd, J = 8.3, 1.7 Hz, 1H), 8.23 (dd, J = 8.1, 1.7 Hz, 1H), 7.72 (dd, J = 8.3, 4.3 Hz, 1H), 7.65 (s, 1H),
7.65 (dd, J = 8.2, 4.3 Hz, 1H). 13C NMR (CDCl3, 101 MHz) δ 151.5 (s, C-9), 150.8 (s, C-2), 136.2 (s, C-7),
130.5 (s, C-4), 127.5 (s, C-6), 123.8 (s, C-3/8), 123.6 (s, C-3/8), 115.1 (q, J = 1.7 Hz, C-5), tertiary
carbons (C-11, C-12, C-4a, C-6a and OCF3) not detected because of low signal intensity. 19F NMR
(CDCl3, 376 MHz): δ -57.50 (s, CF3). HRMS (m/z, ESI+): 265.060 (cal.: 265.058) [M+H]+, 287.040 (cal.:
287.040) [M+Na]+, 551.092 (cal.: 551.091) [2M + Na]+. CHN analysis (%): C 59.17 (calcd.: 59.10), H
3.00 (2.67), N 10.27 (10.60).
8-Nitro-6-(pentafluorosulfanyl) quinoline (2e) (reaction type A)
Yellow solid. 1H NMR (CDCl3, 400 MHz): δ 9.20 (dd, J = 4.2, 1.7 Hz, H-2), 8.49 (d, J = 2.3 Hz, H-5/7),
8.42 (dd, J = 8.4, 1.6 Hz, H-4), 8.37 (d, J = 2.4 Hz, H-5/7), 7.72 (dd, J = 8.4, 4.2 Hz, H-3). 19F NMR (CDCl3,
376 MHz): δ 82.05–80.07 (quin, J = 151.1 Hz, 1F, axial F), 63.97 (d, J = 151.1 Hz, 4F, basal F). HRMS
(ESI+), m/z: 301.007 (calcd.: 301.007) [M+H]+, 322.990 (calcd.: 322.989) [M+Na]+, 622.990 (calcd.:
622.988) [2M+Na]+. IR (ATR): 3100 (br w), 2918 (br w), 1596 (w), 1538 (s), 1495 (m), 1422 (w), 1394
(w), 1358 (m), 1322 (w), 1208 (w), 1148 (w), 1102 (m), 910 (m), 898 (m), 888 (m), 869 (m), 842 (s),
809 (s), 793 (s), 739 (m), 689 (w), 659 (m), 642 (w), 605 cm−1 (m).
8-Amino-6-(pentafluorosulfanyl) quinoline (3e) (reaction type B)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 8.85 (dd, J = 3.9, 2.0 Hz, H-2), 8.18–8.09 (m, H-4), 7.55
(dd, J = 4.3, 2.1 Hz, H-5/7), 7.54–7.42 (m, H-3), 7.21 (dd, J = 4.4, 2.2 Hz, H-5/7), 5.21 (s, NH2). 19F NMR
(CDCl3, 376 MHz): δ 85.10 (quin, J = 150.6, 149.1 Hz, 1F, axial F), 63.14 (d, J = 150.2 Hz, 4F, basal F).
8

HRMS (ESI+), m/z: 271.032 (calcd.: 271.033) [M+H]+, 293.016 (calcd.: 293.015) [M+Na]+. IR (ATR):
3476 (m), 3376 (w), 3347 (s), 1621 (m), 1596 (m), 1507 (s), 1463 (w), 1421 (w), 1385 (m), 1334 (w),
1247 (w), 1154 (w), 1137 (w), 1106 (w), 928 (m), 884 (m), 844 (s), 819 (s), 773 (s), 729 (m), 660 cm−1
(m).
5-(Pentafluorosulfanyl)-1,10-phenanthroline (4e) (reaction type A)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 9.24 (dd, J = 4.3, 1.8 Hz, H-9), 9.18 (dd, J = 4.2, 1.4 Hz, H-
2), 8.82–8.74 (m, H-4), 8.38 (s, H-6), 8.30 (dd, J = 8.3, 1.6 Hz, H-7), 7.71 (dd, J = 8.9, 4.2 Hz, H-3), 7.68
(dd, J = 8.0, 4.4 Hz, H-8). 13C NMR (CDCl3, 101 MHz) δ 153.2 (s, C-9), 150.6 (s, C-2), 149.6 (m, C-5),
147.0 (s, C-11), 146.3 (s, C-12), 137.5 (s, C-7), 134.4 (m, C-4), 129.2 (m, C-6), 125.4 (s, C-6a), 124.2 (s,
C-8), 123.9 (s, C-3), 123.8 (s, C-4a). 19F NMR (CDCl3, 376 MHz): δ 85.78 (quin, J = 147.4 Hz, 1F, axial F),
70.29 (d, J = 149.4 Hz, 4F, basal F). HRMS (m/z, ESI+): 307.030 (calcd.: 307.032) [M+H]+, 329.011
(calcd.: 329.014) [M+Na]+. CHNS analysis (%): C 46.82 (calcd.: 47.06), H 2.70 (2.30), N 9.01 (9.15), S
9.98 (10.47).
8-Nitro-5-(trifluoromethylthio) quinoline (2f)
5-Amino quinoline (CAS 611-34-7): Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 8.87 (m, H-2), 8.16 (m,
H-4), 7.56 (m, H-8), 7.49 (m, H-7), 7.29 (m, H-3), 6.80 (m, H-6), 4.29 (s, NH2). Using a different
procedure, 5-amino quinoline has been described and characterized among others by 1H NMR in
[26]. These data are consistent.
5-(Trifluoromethylthio) quinoline: Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 8.66 (dd, J = 4.2, 1.7
Hz, H-2), 8.43 (d, J = 8.6, H-4), 7.97 (d, J = 8.5 Hz, H-8), 7.65 (d, J = 7.3 Hz, H-6), 7.35 (dd, J = 8.5, 7.2
Hz, H-7), 7.14 (dd, J = 8.6, 4.2 Hz, H-3). 19F NMR (CDCl3, 376 MHz): δ -42.44 (s, CF3).
8-Nitro-5-(trifluoromethylthio) quinoline: Yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.99 (dd, J = 4.2,
1.6 Hz, H-2), 8.78 (dd, J = 8.7, 1.6 Hz, H-4), 8.06 (d, J = 7.7 Hz, H-6/7), 7.95 (d, J = 7.8 Hz, H-6/7), 7.65
(dd, J = 8.7, 4.2 Hz, H-3). 19F NMR (CDCl3, 376 MHz): δ -41.62 (s, CF3). HRMS (m/z, ESI+): 275.01 (calcd.:
275.01) [M+H]+, 296.99 (calcd.: 296.99) [M+Na]+, 570.99 (calcd.: 570.99) [2M + Na]+.
8-Amino-5-(trifluoromethylthio) quinoline (3f) (reaction type B)
Colourless solid. 1H NMR (CDCl3, 400 MHz): δ 8.80 (dd, J = 4.2, 1.5 Hz, H-2), 8.76 (d, J = 8.6 Hz, H-4),
7.80 (d, J = 8.0 Hz, H-6/ 7), 7.55 (dd, J = 8.6, 4.2 Hz, H-3), 6.90 (d, J = 8.0 Hz, H-6/ 7), 5.52 (s, NH2). 19
NMR (CDCl3, 376 MHz): δ -43.93 (s, CF3).
F
5-(Trifluoromethylthio)-1,10-phenanthroline (4f) (reaction type A)
Colourless solid. 1H NMR (CDCl3, 400 MHz): δ 9.15 (dd, J = 4.3, 1.7 Hz, H-9), 9.13 (dd, J = 4.3, 1.7 Hz, H-
2), 8.76 (dd, J = 8.4, 1.5 Hz, H-4), 8.21 (s, H-6), 8.15 (dd, J = 8.1, 1.7 Hz, H-7), 7.64 (dd, J = 8.4, 4.3 Hz,
H-3), 7.56 (dd, J = 8.1, 4.4 Hz, H-8). 13C NMR (CDCl3, 176 MHz) δ 152.0 (s, C-9), 150.6 (s, C-2), 146.9
(s, C-11), 146.3 (s, C-12), 139.0 (s, C-6), 136.2 (s, C-7), 134.3 (s, C-4), 129.5 (s, C-4a), 129.0 (q, J = 309.8
Hz, C-5), 127.3 (s, C-6a), 123.5 (s, C-3/8), 123.5 (s, C-3/8), 120.4 (q, C-5, J = 2.0 Hz). 19F NMR (CDCl3,
376 MHz): δ -41.82 (s, CF3). HRMS (m/z, ESI+): 281.034 (calcd.: 281.035) [M+H]+, 583.042 (calcd.:
583.046) [2M + Na]+. CHNS analysis (%): C 55.57 (calcd.: 55.71), H 2.41 (2.52), N 10.00 (10.00), S 11.61
(11.44).
5-Fluoro-2-methyl-8-nitro quinoline (5a, CAS 1420793-52-7) (reaction type C)
Yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.36 (d, J = 8.7 Hz, H-4), 8.02 (dd, J = 8.5, 5.2 Hz, H-7), 7.48
(d, J = 8.7 Hz, H-3), 7.19 (dd, J = 8.6 Hz, H-6), 2.79 (s, 3H, CH3). 19F NMR (CDCl3, 376 MHz): δ -113.26
(dd, J = 8.7, 5.2 Hz). HRMS (m/z, ESI+): 207.056 (calcd.: 207.056) [M+H]+, 229.037 (calcd.: 229.038) [M
+ Na]+.
9

8-Amino-5-fluoro-2-methyl quinoline (6a, CAS 1393179-68-4) (reaction type D)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 8.18 (d, J = 8.6 Hz, H-4), 7.26 (d, J = 8.5 Hz, H-3), 6.94 (dd,
J = 9.7, 8.4 Hz, H-6), 6.74 (dd, J = 8.3, 5.0 Hz, H-7), 4.79 (s, NH2), 2.70 (s, CH3). 19F NMR (CDCl3, 376
MHz): δ -137.33 (dd, J = 9.8, 5.0 Hz). HRMS (m/z, ESI+): 177.084 (calcd.: 177.082) [M+H]+, 199.067
(calcd.: 199.064) [M + Na]+.
5-Fluoro-2-methyl-1,10-phenanthroline (8a) (reaction type A)
Colorless solid. 1H NMR (CDCl3, 400 MHz): δ 9.03 (dd, J = 4.4, 1.7 Hz, H-9), 8.25 (d, J = 8.4 Hz, H-4),
8.01 (dd, J = 8.1, 1.7 Hz, H-7), 7.46 (dd, J = 8.1, 4.4 Hz, H-8), 7.44 (d, J = 8.4 Hz, H-3), 7.19 (d, J = 10.2
Hz, H-6). 13C NMR (CDCl3, 101 MHz) δ 160.3 (s, C-2), 155.5 (d, C-5, J = 255.8 Hz), 149.0 (s, C-9), 146.1
(d, C-12, J = 5.1 Hz), 143.1 (s, C-11), 135.1 (d, C-7, J = 6.0 Hz), 129.1 (d, C-4, J = 4.8 Hz), 127.8 (d, C-6a,
J = 10.9 Hz), 123.3 (d, J = 1.9 Hz, C-3), 122.8 (s, C-8), 118.8 (d, C-4a, J = 19.5 Hz), 106.2 (d, C-6, J = 20.4
Hz), 25.5 (s, CH3). 19F NMR (CDCl3, 376 MHz): δ -123.55 (d, J = 10.2 Hz). HRMS (m/z, ESI+): 213.084
(calcd.: 213.082) [M+H]+, 235.064 (calcd.: 235.066) [M+Na]+. CHN analysis (%): C 73.65 (calcd.: 73.57),
H 3.88 (4.27), N 13.06 (13.20).
2-Methyl-8-nitro-6-(trifluoromethyl) quinoline (5c, CAS 2012521-38-7) (reaction type C)
Yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.29–8.26 (m, H-5/7), 8.22 (d, J = 8.5 Hz, H-4), 8.12 (d, J =
1.9 Hz, H-5/7), 7.54 (d, J = 8.5 Hz, H-3), 2.82 (s, CH3). 19F NMR (CDCl3, 376 MHz): δ -62.13 (s, CF3).
Using a different procedure, 5c has been described and characterized by 1H NMR in [27]. These data
are consistent.
8-Amino-2-methyl-6-(trifluoromethyl) quinoline (6c, CAS 1286757-17-2) (reaction type D)
Colourless solid. 1H NMR (CDCl3, 400 MHz): δ 8.01 (d, J = 8.4 Hz, H-4), 7.38 (s, H-5/7), 7.33 (d, J = 8.4
Hz, H-3), 7.01 (d, J = 1.8 Hz, H-7/5), 5.15 (s, 2H, NH2), 2.74 (s, 3H, CH3).19F NMR (CDCl3, 376 MHz): δ
-62.56 (s, CF3). Using a different procedure, 6c has been described and characterized among others
by 1H NMR in [28]. These data are consistent.
6-(Trifluoromethyl)-2-methyl-1,10-phenanthroline (7c) (reaction type A)
Colourless solid. 1H NMR (CDCl3, 400 MHz): δ 9.29 (d, J = 4.2 Hz, H-9), 8.56 (d, J = 8.3 Hz, H-7), 8.19 (d,
J = 8.3 Hz, H-4), 8.17 (s, H-5), 7.72 (dd, J = 8.4, 4.3 Hz, H-8), 7.58 (d, J = 8.2 Hz, H-3), 2.96 (s, 3H, CH3).
13C NMR (CDCl3, 101 MHz) δ 162.5 (s, C-2), 150.6 (s, C-9), 146.3 (s, C-11/12), 145.5 (s, C-12/11), 137.5
(s, C-4/7), 133.6 (s, C-7/4), 126.5 (q, J = 5.9 Hz, C-5), 124.9 (s, C-3/8), 124.3 (s, C-6a), 124.3 (s, C-4a),
123.9 (q, J = 273.2 Hz, CF3), 123.5 (C-3/8), 26.0 (s, CH3). 19F NMR (CDCl3, 376 MHz): δ -59.84 (s, CF3).
HRMS (m/z, ESI+): 263.082 (calcd.: 263.079) [M+H]+, 285.064 (calcd.: 285.061) [M+Na]+. CHNS analysis
(%): C 63.82 (calcd.: 64.12), H 3.64 (3.46), N 10.41 (10.68).
2-Methyl-8-nitro-6-(pentafluorosulfanyl) quinoline (5e) (reaction type C)
Yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.40 (d, J = 2.4 Hz, H-5/7), 8.29 (d, J = 2.4 Hz, H-5/7), 8.23
(d, J = 8.6 Hz, H-4), 7.56 (d, J = 8.6 Hz, H-3), 2.82 (s, 3H, CH3). 19F NMR (CDCl3, 376 MHz): δ 81.71 (quin,
JF-F = 151.2 Hz, 1F, axial F), 64.15 (d, 4F, JF-F = 150.6 Hz, 4F, basal F). HRMS (m/z, ESI+): 315.023 (calcd.:
315.022) [M+H]+, 337.006 (calcd.: 337.004) [M + Na]+.
8-Amino-2-methyl-6-(pentafluorosulfanyl) quinoline (6e) (reaction type D)
Colourless solid. 1H NMR (CDCl3, 400 MHz): δ 7.90 (d, J = 8.4 Hz, H-4), 7.47 (d, J = 2.2 Hz, H-5/7), 7.26
(d, J = 8.4 Hz, H-3), 7.16 (d, J = 2.3 Hz, H-5/7), 5.18 (s, 2H, NH2), 2.70 (s, 3H, CH3). 19F NMR (CDCl3, 376
MHz): δ 85.79 (quin, J = 149.9 Hz, 1F, axial F), 63.40 (d, J = 149.6 Hz, 4F, basal F). HRMS (m/z, ESI+):
285.049 (calcd.: 285.048) [M+H]+, 307.030 (calcd.: 307.030) [M + Na]+.
10

2-Methyl-6-(pentafluorosulfanyl)-1,10-phenanthroline (7e) (reaction type A)
Colourless solid. 1H NMR (CDCl3, 400 MHz): δ 9.24 (dd, J = 4.2, 1.3 Hz, H-9), 8.84 (d, J = 8.5 Hz, H-7),
8.39 (s, H-5), 8.21 (d, J = 8.2 Hz, H-4), 7.72 (dd, J = 8.8, 4.2 Hz, H-8), 7.60 (d, J = 8.2 Hz, H-3), 2.97 (s,
3H, CH3). 13C NMR (CDCl3, 101 MHz) δ 163.2 (s, C-2), 150.6 (s, C-9), 146.6 (C-11/C-12), 145.9
(C-12/C-11), 137.6 (s, C-4), 134.5–134.2 (m, C-7), 129.1 (m, C-5), 125.0 (s, C-8), 124.0–123.9 (m, C-4a),
123.6 (s, C-3), 123.5 (m, C-6a), 26.3 (s, CH3). 19F NMR (CDCl3, 376 MHz): δ 86.31 (quin, J = 149.3 Hz,
1F, axial F), 70.49 (d, J = 149.3 Hz, 4F, basal F). HRMS (m/z, ESI+): 321.052 (calcd.: 321.048) [M+H]+.
CHNS analysis (%): C 48.97 (calcd.: 48.75), H 3.22 (2.83), N 8.43 (8.75), S 9.67 (10.01).
6-Fluoro-2-methyl-1,10-phenanthroline (8a) (reaction type C)
Colourless solid. 1H NMR (CDCl3, 400 MHz): δ 9.26 (dd, J = 4.4, 1.7 Hz, H-9), 8.51 (dd, J = 8.2, 1.7 Hz, H-
7), 8.07 (d, J = 8.2 Hz, H-4), 7.68 (dd, J = 8.2, 4.4 Hz, H-8), 7.51 (d, J = 8.2 Hz, H-3), 7.39 (d, J = 10.2 Hz,
H-5), 2.93 (s, CH3). 13C NMR (CDCl3, 101 MHz) δ 158.3 (d, J = 2.6 Hz, C-2), 154.6 (d, J = 254.5 Hz, C-6),
150.8 (s, C-9), 146.1 (d, J = 4.8 Hz, C-11), 142.9 (d, J = 1.3 Hz, C-12), 135.4 (d, J = 5.6 Hz, C-7), 129.1 (d,
J = 5.1 Hz, C-4), 125.5 (d, J = 10.6 Hz, C-4a), 123.8 (s, C-3), 122.4 (d, J = 2.2 Hz, C-8), 120.9 (d, J = 19.4
Hz, C-6a), 107.2 (d, J = 20.2 Hz, C-5), 25.3 (s, C-13, CH3). 19F NMR (CDCl3, 376 MHz): δ -125.25 (d, J =
10.2 Hz). HRMS (m/z, ESI+): 213.079 (calcd.: 213.082) [M+H]+, 235.061 (calcd.: 235.066) [M+Na]+.
CHNS analysis (%): C 73.79 (calcd.: 73.57), H 3.92 (4.27), N 12.96 (13.20).
2-Methyl-6-(trifluoromethylthio)-1,10-phenanthroline (8f) (reaction type C)
Colourless solid. 1H NMR (CDCl3, 400 MHz): δ 9.20 (dd, J = 4.3, 1.7 Hz, H-9), 8.83 (dd, J = 8.4, 1.4 Hz, H-
7), 8.24 (s, H-5), 8.09 (d, J = 8.2 Hz, H-4), 7.67 (dd, J = 8.4, 4.3 Hz, H-8), 7.50 (d, J = 8.2 Hz, H-3), 2.91 (s,
3H, CH3). 13C NMR (CDCl3, 101 MHz) δ 162.1 (s, C-2), 150.8 (s, C-9), 146.8 (s, C-11/12), 146.4 (s, C-
12/11), 139.3 (s, C-5), 136.6 (s, C-4/7), 134.6 (s, C-7/4), 130.0 (C-6a), 129.3 (q, J = 310.8 Hz, CF3),
125.7 (C-4a), 124.4 (s, C-3/8), 123.5 (C-3/8), 119.4 (q, J = 1.9 Hz, C-6), 26.1 (s, C-13, CH3). 19F NMR
(CDCl3, 376 MHz): δ -41.95 (s, CF3). HRMS (m/z, ESI+): 295.047 (calcd.: 295.051) [M+H]+, 317.029
(calcd.: 317.033) [M+Na]+. CHNS analysis (%): C 57.01 (calcd.: 57.14), H 3.34 (3.08), N 9.29 (9.52), S
11.20 (10.89).
5-Fluoro-2,9-dimethyl-1,10-phenanthroline (9a) (reaction type C)
Colourless solid. 1H NMR (CDCl3, 400 MHz): δ 8.36 (d, J = 8.4 Hz, H-4), 8.01 (d, J = 8.2 Hz, H-7), 7.52 (d,
J = 8.4 Hz, H-3), 7.44 (d, J = 8.2 Hz, H-8), 7.28 (d, J = 10.1 Hz, H-6), 2.93 (s, H-13, CH3), 2.89 (s, H-14,
CH3). 13C NMR (CDCl3, 101 MHz) δ 160.6 (s, C-9), 158.6 (d, J = 2.6 Hz, C-2), 155.4 (d, J = 254.0 Hz, C-5),
146.1 (d, J = 4.9 Hz, C-12), 142.9 (d, J = 1.3 Hz, C-11), 135.8 (d, J = 5.6 Hz, C-7), 129.7 (d, J = 5.0 Hz, C-
4), 126.1 (d, J = 10.8 Hz, C-6a), 124.1 (d, J = 0.7 Hz, C-8), 123.6 (d, J = 2.1 Hz, C-3), 119.3 (d, J = 19.4 Hz,
C-4a), 106.6 (d, J = 20.3 Hz, C-6), 26.1 (s, C-13, CH3), 25.9 (s, C-14, CH3). 19F NMR (CDCl3, 376 MHz): δ
-125.24 (d, J = 10.1 Hz).
Acknowledgement
We thank the German Research Foundation (DFG) (GRK 1582) for financial support. Jan Hormann and
Julian Heinrich are acknowledged for measuring ESI mass spectra. All members of the Kulak Group
are acknowledged for proofreading of this article.
11

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Figure 1: Numbering scheme for 2,9-dimethyl-1,10-phenanthroline (the same applies to 2-methyl 1,10-phenanthroline
and 1,10-phenanthroline).
14

Scheme 1: Synthesis of fluorine-containing nitro quinoline derivatives and 1,10-phenanthroline derivatives via modified
Skraup reaction conditions (3f was obtained applying a different route, cf. text).
Scheme 2: Synthesis of fluorine-containing 8-amino-2-methylquinolines 6 and routes for the synthesis of
regioisomeric fluorine-containing 2-methyl-1,10-phenanthrolines 7 and 9 (A: Skraup reaction, C: Doebner–
von Miller reaction) as well as 5-fluoroneocuproine 9.
15

Table 1: Synthesis of fluorinated quinoline and phenanthroline derivatives
Entry Starting material Reaction type (Aa, Bb, Cc, Dd) Product
Yield (%)e
A
C
A
A
C
A
A
C
B
B
B
B
B
B
A
C
A
A
A
A
A
C
D
D
D
A
C
A
A
2a
5a
2b
2c
5c
2d
2e
5e
3a
3b
3c
3d
3e
3f
4a
8a
4b
4c
4d
4e
4f
19 (41)g
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a
1b
1c
1d
1e
28
33
41
19
39
38
24
77 (89)g
63
92
66
88
89
33f
38f
41f
35f
44
25f
44
31h
78
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
21
22
23
24
25
26
3f
8f
5a
5c
5e
6a
6c
6e
7a
9a
7c
7e
89
83
33
28
48f
32f
6a
27
28
29
6c
6e
aSkraup reaction with acrolein diethyl acetal, tris(arsen(V)oxide) pentahydrate, sulfuric acid (70%).
bReduction with stannous chloride dihydrate, hydrochloric acid (32%).
cDoebner–von Miller reaction with croton aldehyde, tris(arsen(V)oxide) pentahydrate, sulfuric acid (70%).
dReduction with hydrazinium hydroxide, Pd/C (10%).
eIsolated by column chromatgraphy (Skraup reaction) and precipitation (reduction), respectively.
fIsolated by sublimation.
gYield (%) in literature.
hBased on conversion (64%).
16